tbuckley/cabot-search huggingface dataset:
Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma
Authors: Holly Lee, Sungwoo Ahn, Ranjan Maity, Noemie Leblay, Bachisio Ziccheddu, Marietta Truger, Monika Chojnacka, Anthony Cirrincione, Michael Durante, Remi Tilmont, Elie Barakat, Mansour Poorebrahim, Sarthak Sinha, John McIntyre, Angela M.Y. Chan, Holly Wilson, Shari Kyman, Amrita Krishnan, Ola Landgren, Wencke Walter, Manja Meggendorfer, Claudia Haferlach, Torsten Haferlach, Hermann Einsele, Martin K. Kortüm, Stefan Knop, Jean Baptiste Alberge, Andreas Rosenwald, Jonathan J. Keats, Leo Rasche, Francesco Maura, Paola Neri, Nizar J. Bahlis
Journal: Nature Medicine (2023)

Abstract B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
Effects of AFQ056 on language learning in fragile X syndrome
Authors: Elizabeth Berry-Kravis, Leonard Abbeduto, Randi Hagerman, Christopher S. Coffey, Merit Cudkowicz, Craig A. Erickson, Andrea McDuffie, David Hessl, Lauren Ethridge, Flora Tassone, Walter E. Kaufmann, Katherine Friedmann, Lauren Bullard, Anne Hoffmann, Jeremy Veenstra-VanderWeele, Kevin Staley, David Klements, Michael Moshinsky, Brittney Harkey, Jeff Long, Janel Fedler, Elizabeth Klingner, Dixie Ecklund, Michele Costigan, Trevis Huff, Brenda Pearson
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.
<i>Notes from the Field</i>: Outbreak of Norovirus Illness Caused by Consumption of Oysters Harvested from Galveston Bay, Texas — November–December 2022
Authors: Morgan Jibowu, Kaitlin Driesse, Sarah May, Amanda Wright, Tyler Swate, Caitlin Cotter
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

DSHS) Public Health Region 6/5 South (PHR 6/5S) and DSHS Consumer Protection Division were notified by Galveston County Health District of 10 consumer complaints of illness after consumption of raw (nine complaints) and smoked (one) oysters at local restaurants during November 27-December 4. Signs and symptoms began within 8 hours after consumption and included diarrhea, nausea, or vomiting.Initially, no consumers sought medical care.Oyster tags from three associated restaurant inspections determined that oysters were from Oyster Harvest Area TX 1 (TX 1) in Galveston Bay, Texas.Also on December 7, the Florida Department of Health contacted DSHS to report its investigation of 37 cases of gastrointestinal illness associated with raw oyster consumption.The investigation also identified several TX 1 oyster tags.On December 8, 2022, representatives from the DSHS Foodborne Illness Team, Seafood and Aquatic Life Operations Branch, Consumer Protection Division, PHR 6/5S, and Galveston County Health District met to discuss the increase in reports of oyster-related gastrointestinal illness.It was determined that TX 1 had been the only area open for shellfish harvesting in Galveston Bay since December 1, 2022.Based on the increased reports of gastrointestinal illness and National Shellfish Sanitation Program (NSSP) guidelines, DSHS Consumer Protection Division closed TX 1 on December 8 and recalled all oysters harvested in TX 1 during November 17-December 7 (1,2).On December 9, the Florida Department of Health notified DSHS that three associated clinical specimens had tested positive for norovirus GII (Figure).DSHS compiled resources for local health departments, restaurants, and consumers to provide education on the transmission and prevention of norovirus and proper disinfection protocols (Figure) and informed the Interstate Shellfish Sanitation Conference, which notified other member states.An outbreak-associated case was defined as the onset of diarrhea, nausea, or vomiting within 72 hours after consumption of oysters harvested from TX 1 during November 17-December 7, 2022 (the recall period).A press release was issued, which led to additional consumer complaints and highlighted the importance of public communication regarding foodborne outbreaks.
Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti–PD-1 resistance
Authors: Ashwin Ajith, Kenza Mamouni, Daniel D. Horuzsko, Abu Musa, Amiran K. Dzutsev, Jennifer R. Fang, Ahmed Chadli, Xingguo Zhu, Iryna Lebedyeva, Giorgio Trinchieri, Anatolij Horuzsko
Journal: Journal of Clinical Investigation (2023)

The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.
Theranostic gold-in-gold cage nanoparticles enable photothermal ablation and photoacoustic imaging in biofilm-associated infection models
Authors: Maryam Hajfathalian, Christiaan R. de Vries, Jessica C. Hsu, Ahmad Amirshaghaghi, Yuxi C. Dong, Zhi Ren, Yuan Liu, Yue Huang, Yong Li, Simon A.B. Knight, Pallavi Jonnalagadda, Aimen Zlitni, Elizabeth A. Grice, Paul L. Bollyky, Hyun Koo, David P. Cormode
Journal: Journal of Clinical Investigation (2023)

Biofilms are structured communities of microbial cells embedded in a self-produced matrix of extracellular polymeric substances. Biofilms are associated with many health issues in humans, including chronic wound infections and tooth decay. Current antimicrobials are often incapable of disrupting the polymeric biofilm matrix and reaching the bacteria within. Alternative approaches are needed. Here, we describe a unique structure of dextran coated gold in a gold cage nanoparticle that enables photoacoustic and photothermal properties for biofilm detection and treatment. Activation of these nanoparticles with a near infrared laser can selectively detect and kill biofilm bacteria with precise spatial control and in a short timeframe. We observe a strong biocidal effect against both Streptococcus mutans and Staphylococcus aureus biofilms in mouse models of oral plaque and wound infections respectively. These effects were over 100 times greater than that seen with chlorhexidine, a conventional antimicrobial agent. Moreover, this approach did not adversely affect surrounding tissues. We conclude that photothermal ablation using theranostic nanoparticles is a rapid, precise, and non-toxic method to detect and treat biofilm-associated infections.
Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src
Authors: Elin Sjöberg, Marit Melssen, Mark Richards, Yindi Ding, Catarina Chanoca, Dongying Chen, Emmanuel Nwadozi, Sagnik Pal, Dominic T. Love, Takeshi Ninchoji, Masabumi Shibuya, Michael Simons, Anna Dimberg, Lena Claesson-Welsh
Journal: Journal of Clinical Investigation (2023)

Endothelial phospholipase Cγ (PLCγ) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLCγ was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLCγ expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLCγ was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLCγ (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo- and immunotherapy. Mechanistically, pY1173/PLCγ signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLCγ/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLCγ and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLCγ pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.
Real-world effectiveness of airway clearance techniques in children with cystic fibrosis
Authors: Nicole Filipow, Sanja Stanojevic, Emma Raywood, Harriet Shannon, Gizem Tanriver, Kunal Kapoor, Helen Douglas, Gwyneth Davies, Rachel O'Connor, Nicky Murray, Eleanor Main
Journal: European Respiratory Journal (2023)

Background Cystic fibrosis (CF) is commonly characterised by thick respiratory mucus. From diagnosis, people with CF are prescribed daily physiotherapy, including airway clearance techniques (ACTs). ACTs consume a large proportion of treatment time, yet the efficacy and effectiveness of ACTs are poorly understood. This study aimed to evaluate associations between the quality and quantity of ACTs and lung function in children and young people with CF. Methods Project Fizzyo, a longitudinal observational cohort study in the UK, used remote monitoring with electronic pressure sensors attached to four different commercial ACT devices to record real-time, breath-by-breath pressure data during usual ACTs undertaken at home over 16 months in 145 children. ACTs were categorised either as conformant or not with current ACT recommendations based on breath pressure and length measurements, or as missed treatments if not recorded. Daily, weekly and monthly associations between ACT category and lung function were investigated using linear mixed effects regression models adjusting for clinical confounders. Results After exclusions, 45 224 ACT treatments (135 individuals) and 21 069 days without treatments (141 individuals) were analysed. The mean± sd age of participants was 10.2±2.9 years. Conformant ACTs (21%) had significantly higher forced expiratory volume in 1 s (FEV 1 ) (mean effect size 0.23 (95% CI 0.19–0.27) FEV 1 % pred per treatment) than non-conformant (79%) or missed treatments. There was no benefit from non-conformant or missed treatments and no significant difference in FEV 1 between them (mean effect size 0.02 (95% CI −0.01–0.05) FEV 1 % pred per treatment). Conclusions ACTs are beneficial when performed as recommended, but most people use techniques that do not improve lung function. Work is needed to monitor and improve ACT quality and to increase the proportion of people doing effective airway clearance at home.
The impact of the immune system on lung injury and regeneration in COPD
Authors: Theodore S. Kapellos, Thomas M. Conlon, Ali Önder Yildirim, Mareike Lehmann
Journal: European Respiratory Journal (2023)

COPD is a devastating respiratory condition that manifests via persistent inflammation, emphysema development and small airway remodelling. Lung regeneration is defined as the ability of the lung to repair itself after injury by the proliferation and differentiation of progenitor cell populations, and becomes impaired in the COPD lung as a consequence of cell intrinsic epithelial stem cell defects and signals from the micro-environment. Although the loss of structural integrity and lung regenerative capacity are critical for disease progression, our understanding of the cellular players and molecular pathways that hamper regeneration in COPD remains limited. Intriguingly, despite being a key driver of COPD pathogenesis, the role of the immune system in regulating lung regenerative mechanisms is understudied. In this review, we summarise recent evidence on the contribution of immune cells to lung injury and regeneration. We focus on four main axes: 1) the mechanisms via which myeloid cells cause alveolar degradation; 2) the formation of tertiary lymphoid structures and the production of autoreactive antibodies; 3) the consequences of inefficient apoptotic cell removal; and 4) the effects of innate and adaptive immune cell signalling on alveolar epithelial proliferation and differentiation. We finally provide insight on how recent technological advances in omics technologies and human ex vivo lung models can delineate immune cell-epithelium cross-talk and expedite precision pro-regenerative approaches toward reprogramming the alveolar immune niche to treat COPD.
B-cell-derived IL-10 promotes allergic sensitization in asthma regulated by Bcl-3
Authors: Guojun Qian, Wenxia Jiang, Donglin Sun, Zhun Sun, Anning Chen, Hongwei Fang, Jingyao Wang, Yongzhong Liu, Zhinan Yin, Haiming Wei, Hao Fang, Xiaoren Zhang
Journal: Cellular and Molecular Immunology (2023)
Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children
Authors: Temesgen E. Andargie, Katerina Roznik, Neelam Redekar, Tom Hill, Weiqiang Zhou, Zainab Apalara, Hyesik Kong, Oren Gordon, Rohan Meda, Woojin Park, Trevor S. Johnston, Yi Wang, Sheila Brady, Hongkai Ji, Jack A. Yanovski, Moon K. Jang, Clarence M. Lee, Andrew H. Karaba, Andrea L. Cox, Sean Agbor-Enoh
Journal: Journal of Clinical Investigation (2023)

Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomic analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared to pediatric healthy controls (pHC) and pCOVID-19, MIS-C patients had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and non-hematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Non-hematopoietic tissue cfDNA levels demonstrated significant inter-individual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the innate immune cells cfDNA in MIS-C correlated with levels of innate immune inflammatory cytokines and non-hematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for multi-system pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multi-organ inflammatory conditions.
Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML
Authors: Yongping Zhang, Shuting Jiang, Fuhong He, Yuanyuan Tian, Haiyang Hu, Li Gao, Lin Zhang, Aili Chen, Yixin Hu, Liyan Fan, Chun Yang, Bi Zhou, Dan Liu, Zihan Zhou, Yanxun Su, Lei Qin, Yi Wang, Hailong He, Jun Lu, Peifang Xiao, Shaoyan Hu, Qian-Fei Wang
Journal: Genome biology (2023)

Cancer patients can achieve dramatic responses to chemotherapy yet retain resistant tumor cells, which ultimately results in relapse. Although xenograft model studies have identified several cellular and molecular features that are associated with chemoresistance in acute myeloid leukemia (AML), to what extent AML patients exhibit these properties remains largely unknown.We apply single-cell RNA sequencing to paired pre- and post-chemotherapy whole bone marrow samples obtained from 13 pediatric AML patients who had achieved disease remission, and distinguish AML clusters from normal cells based on their unique transcriptomic profiles. Approximately 50% of leukemic stem and progenitor populations actively express leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures, respectively. These clusters have a higher chance of tolerating therapy and exhibit an enhanced metabolic program in response to treatment. Interestingly, the transmembrane receptor CD69 is highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (named the CD69+ HSC-like subpopulation). Furthermore, overexpression of CD69 results in suppression of the mTOR signaling pathway and promotion of cell quiescence and adhesion in vitro. Finally, the presence of CD69+ HSC-like cells is associated with unfavorable genetic mutations, the persistence of residual tumor cells in chemotherapy, and poor outcomes in independent pediatric and adult public AML cohorts.Our analysis reveals leukemia stem cell and OXPHOS as two major chemoresistant features in human AML patients. CD69 may serve as a potential biomarker in defining a subpopulation of chemoresistant leukemia stem cells. These findings have important implications for targeting residual chemo-surviving AML cells.
Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems
Authors: Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini
Journal: Nature Aging (2023)
Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA
Authors: Moonsun Sa, Eun-Seon Yoo, Wuhyun Koh, Mingu Gordon Park, Hyun-Jun Jang, Yong Ryoul Yang, Mridula Bhalla, Jae-Hun Lee, Jiwoon Lim, Woojin Won, Jea Kwon, Joon-Ho Kwon, Yejin Seong, Byungeun Kim, Heeyoung An, Seung Eun Lee, Ki Duk Park, Pann-Ghill Suh, Jong-Woo Sohn, C. Justin Lee
Journal: Nature Metabolism (2023)
Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation
Authors: Jennifer Derrien, Sarah Gastineau, Antoine Frigout, Nils Giordano, Mia Cherkaoui, Victor Gaborit, Rémi Boinon, Elise Douillard, Magali Devic, Florence Magrangeas, Philippe Moreau, Stéphane Minvielle, Cyrille Touzeau, Eric Letouzé
Journal: Nature Cancer (2023)